All patents, applications, publications, test methods, and other materials cited herein are incorporated by reference.
Inflammation is a process that occurs in response to injury or other abnormal stimulation by physical, chemical, or biological agents, with the purpose of helping to overcome the abnormal stimulus. Inflammation involves local tissue reactions and morphologic changes, destruction or removal of injurious material, and the initiation of repair and/or healing. Cardinal signs of active inflammation include redness, heat, swelling, pain, and reduction or loss of function; these signs can present locally and/or systemically.
While the purpose of an inflammatory response is to help the host overcome an abnormal stimulus, inflammatory episodes can have deleterious effects. In the short-term, febrile or painful animals may have reduced feed and water intake, which can create the risk of developing problems related to a negative energy balance or dehydration. Furthermore, some inflammatory episodes can leave long-lasting residual damage, scarring, and reduced functionality.
For example, bovine respiratory disease (BRD) occurs in both dairy and beef cattle and is one of the leading causes of economic loss to the cattle industry throughout the world. Economic losses are attributable to excessive mortality, treatment and prevention costs, and decreased productivity—dairy cattle with clinical or sub-clinical BRD do not gain weight or produce milk as well as healthy animals, and beef cattle with BRD gain less weight, have reduced feed efficiency and often produce a lower grade carcass at slaughter. A direct correlation between pulmonary lesions observed at slaughter and reduced weight gains has been established in cattle with sub-clinical BRD infections. The etiologic agents of BRD are bacterial organisms such as Mannheimia haemolytica, Pasteurella multocida and Histophilus somni. However, in BRD infections, the pulmonary damage that results in death or morbidity is often due to an excessive host inflammatory response to the invading pathogens. In the short term, febrile, painful animals eat and drink less. Furthermore, long-term damage to host tissues occurs, resulting in long-term declines in productivity even after BRD infection has resolved.
Bovine mastitis is considered to be the most costly production disease faced by the dairy industry, costing hundreds of millions of dollars per year. Bovine mastitis is typically caused by infectious agents such as Staphylococcus aureus, Streptococcus species, and Escherichia coli. In response to infection, the mammary gland undergoes an inflammatory process, characterized by warmth, pain, redness, swelling, and impaired function. The affected animal often develops a fever and eats and drinks less. There is a transient decrease in milk production during the acute inflammatory stage, and subsequent milk yield for the remainder of the lactation is reduced as a result of residual inflammatory damage.
In addition to cattle, other species are similarly susceptible to short-term and long-term effects of inflammatory episodes induced by a variety of causes. Regardless of species or causative agent, the damage brought about by inflammation evolves as neutrophils and other inflammatory cells destroy affected tissues. As cell membranes are damaged, arachidonic acid is released. Arachidonic acid is the substrate for the formation of various prostaglandins and other eicosanoids. The release of these biologically active substances is critical to driving the inflammatory response that results in additional inflammatory damage and lesions. Non-steroidal anti-inflammatory drugs (NSAIDs) effectively modulate inflammation by disrupting the arachidonic acid cascade.
Use of NSAIDs is a cornerstone of management of inflammatory processes in human and veterinary medicine. Regardless of the species or organ system affected or the cause, pharmacologic modulation of inflammation offers important quality of life benefits to painful or febrile animals, allowing the affected animal to eat and drink and thus increase the potential for recovery. Furthermore, use of NSAIDs helps to reduce excessive damage that results in long-term reduction of functionality, thus bringing economic benefits to livestock producers.
Flunixin megiumine is the active ingredient in FINADYNE® and BANAMINE® (both available from Schering-Plough Animal Health Corporation). It has emerged as one of the leading NSAIDs in large animal veterinary medicine and is a first choice NSAID for adjunctive therapy of BRD and mastitis in cattle. Flunixin meglumine has been studied extensively in regard to its use in conjunction with antibiotics for the treatment of BRD and mastitis.
Both flunixin meglumine and flunixin base both have very poor lipid solubility. Traditionally, a compound needs to have a moderate degree of lipid solubility in order to be delivered across the lipid layers of the skin. Because of the undesirable solubility characteristics of flunixin meglumine, it presents challenges regarding formulating it into an effective transdermal liquid preparation.
Flunixin meglumine is currently formulated for intravenous injection in cattle using a syringe and needle, which introduces some challenges. Needles present challenges with respect to accumulation and disposal of sharp biowaste material, needle stick hazards for human handlers, and an additional discomfort for animals being treated. Also, the requirement for intravenous injection requires some technical expertise for proper administration. As a result of these requirements for proper administration of flunixin meglumine to cattle, some animals in need may go untreated in the interest of reducing needle waste, protecting human handlers, or because of technical limitations.
Thus, there is a need for an improved formulation and method of administration, such as a formulation for transdermal drug delivery, which addresses these problems. One difficulty faced, however, when attempting to arrive at a transdermal formulation is the fact that the skin has been described as a “black box” with regard to drug delivery. This is due to the lack of knowledge in the mechanisms of drug penetration through the epidermis and partitioning into the underlying layers. Thus far, the boundaries for such properties have not been defined; making it very difficult to predict what compounds can be delivered transdermally. Transdermal systems effective for delivering one compound are almost always ineffective with other compounds and systems and devices that work in one species are almost universally ineffective in other species. Furthermore, due to the presence of stratum corneum barrier, the mass transfer through the skin is usually too slow for rapid, massive systemic absorption. This explains why very few, if not any, of the commercially available transdermal products for human use are designed for immediate drug delivery.
Accordingly, there is a need for stable, transdermal liquid preparation that offers a way for handlers to safely and conveniently administer flunixin to animals in need thereof to ameliorate inflammation, while minimizing the pain and stress to the animal associated with treatment and the potential for injection site tissue damage.